Industry is often faced with the problem that certain reactions must be carried out at low concentration and/or high dilution of one or more of the substrates, typically to avoid side reactions which may lead to the formation of unwanted side products.
Examples of reactions which are often performed at high dilution include cyclization reactions, such as intramolecular macrocyclization reactions for the production of active pharmaceutical ingredients. In such reactions, high substrate concentrations may favour the formation of intermolecular reactions instead of intramolecular reactions, which can lead to polymerization of the substrate in the reaction medium or to the occurrence of other unwanted side-reactions, thereby decreasing the yield to the desired product and the product purity.
Similar unwanted intermolecular side reactions have been observed in certain types of polymerization reactions, for example in the synthesis of cyclic polymers. Enzymatic reactions with substrate inhibition exemplify another type of reactions that are preferably carried out at high dilution of the substrate. Indeed, in such reactions a high substrate concentration may lead to a declining catalytic activity of the enzyme. Yet other types of reactions which favour low concentration of the substrate include reactions wherein high substrate concentrations lead to unwanted precipitation of one or more components within the reaction mixture.
Accordingly, certain reactions are preferably carried out at high dilution of the substrate in order to minimize the formation of unwanted side products. In particular in batch reactions, this requires the use of large amounts of solvent, as frequently used solvent dilution rates mount to 100-1000 L/mol of substrate to permit keeping substrate concentration sufficiently low. In other words, for the production of small quantities of an end product, often the use of large volumes of solvent and the use of large reactor volumes is required, thereby obtaining small reaction product yields per unit volume of reactor.
For a number of reactions, the total amount of solvent required for reaction may be reduced by using a so-called “fed-batch” process, wherein the substrate is gradually added to the reactor and in which the product(s) remain in the reactor until the end of the run. However, such process is only useful if the desired reaction products are stable in the reactor. However, it is not uncommon that the reaction is reversible, thus leading to a too high concentration of substrate which may result in the formation of unwanted side products.
US20040211729 discloses a process and system for recovering oligomers and/or acid catalyst from wash streams using filter membranes, wherein the product stream is removed via a settler. The preferred operation of the process is a batch operation, and in case of a continuous operation there is no recycling of retentate. In addition, the reaction is not performed in dilute conditions.
WO88/05444 discloses a process and system for separation of synthetic water soluble polymers, wherein the polymerization reaction is performed as a batch reaction and wherein the product stream is charged into a membrane unit with recirculation of the permeate obtained after filtration to the reactor.
Thus, there is a need for processes and systems suitable for carrying out reactions which require maintaining one or more of the substrates at a low concentration, more particularly which are equally suitable for reactions wherein the reaction product is not stable in the reactor.